Molecular mechanisms associated with the initiation and progression of atherosclerosis are the focus of this SCOR renewal. Particular emphasis will be upon integration of the molecular and cellular responses of the vessel wall, ranging from the effects of flow on the endothelium, circulating monocytes and subendothelial tissue, lipoprotein interactions with each other, the extracellular matrix and vascular cells, including postprandial lipoproteins in a clinical project, and the structure and regulation of apolipoprotein E. The center comprises 8 projects and 4 core units including one clinical project. Dr. Davies will seek a mechanosensor in endothelial cells, for which a potassium channel is a prime candidate. He will also study flow dependent mass transport, and the way the endothelial cells signal their flow responses to underlying smooth muscle cells. Dr. Giddens will extend his modeling studies of the flow profiles in vascular beds to characterize the spatial relationships between flow, pressure and vessel wall responses assayed by morphology, histochemistry and molecular probes to determine the hemodynamic mechanisms of lesion localization. Dr. Meredith will study LDL, modified by oxidation or hyperlipidemia in its interaction with itself (homogeneous fusion) and with matrix molecules (heterogeneous fusion). Dr. Mazzone will study the early response of the LDL receptor gene to growth activation and the mechanisms involved. Drs. Getz and Reardon will extend studies of apoprotein E structure and function (association with lipoproteins) and the regulation of apoprotein E production by transcriptional and post-transcriptional mechanisms. Dr. Schreiber will continue his experiments on apoprotein E in gonad steroidogenic cells with the emphasis on the role of the apoprotein in providing autocrine or paracrine communication between cells. Drs. Polonsky and Getz will study postprandial lipoproteins (chylomicron remnants, VLDL and HDL in obese and diabetic subjects (type II), emphasizing the function of post heparin lipases and the interaction of these particles with cells of the vessel wall. The four core units are administrative core, antigen/antibody core, lipid and lipoprotein analytical core, and molecular biology core.